Until the mid-1980s, the accepted treatment for coronary atherosclerosis, i.e., narrowing of the coronary artery(ies) was coronary by-pass surgery. While being quite effective and having evolved to a relatively high degree of safety for an invasive procedure, by-pass surgery still involves potentially serious complications and generally results in an extended recovery period.
With the advent of percutaneous transluminal coronary angioplasty (PTCA) in 1977, the scene changed dramatically. Using catheter techniques originally developed for heart exploration, inflatable balloons were deployed to re-open occluded regions in arteries. The procedure was relatively non-invasive, took a short time compared to by-pass surgery and recovery time was minimal. However, PTCA brought with it its own problems including vasospasm, elastic recoil of the stretched arterial wall and restenosis, the re-clogging of the treated artery due to neointimal hyperplasia in the vicinity of the procedure, any of which could undo much of what had been accomplished.
The next improvement, advanced in the mid-1980s, was the use of a stent to maintain a luminal diameter that had been re-established using PTCA. This for all intents and purposes put an end to vasospasm and elastic recoil but did not resolve the issue of restenosis. That is, prior to the introduction of stents, restenosis occurred in about 30 to 50% of patients undergoing PTCA. Stenting reduced this to about 15 to 30%, a substantial improvement but still more than desirable.
In 2003, the drug-eluting stent (DES) was introduced. The drugs initially used with DESs were cytostatic compounds, that is, compounds that curtailed the proliferation of cells that fostered restenosis. With DESs, the occurrence of restenosis was reduced to about 5 to 7%, a relatively acceptable figure. However, the use of DESs engendered yet another complication, late stent thrombosis, the forming of blood clots at some time after the stent was in place. It was hypothesized that the formation of blood clots was most likely due to delayed healing, a side-effect of the use of cytostatic drugs. Thus, other types of drugs were sought to reduce the incidence of late stent thrombosis as well as other complications related to the use of cytostatic agents. A promising solution was found in the anti-proliferative family of compounds, in particular rapamycin and its derivatives, which appeared surprisingly effective. DESs comprising members of the rapamycin family of compounds were extensively studied and several have become commercial products. It was found, however, that, due at least in part to the fact that there are three conjugated double bonds in rapamycin and its pharmaceutically active derivatives, the entire family of rapamycin derivative drugs is sensitive to oxidative and free radical induced degradation. That is, oxygen in and around a DES containing the macrocyclic triene fosters the formation of radical species that in turn initiate auto-oxidation of the triene moiety. The response to this negative property of the compounds was obvious to those skilled in the art: protect the rapamycin derivatives by including a pharmaceutically acceptable antioxidant with the drug both as an isolated solid as synthesized and purified and in a drug reservoir layer containing the rapamycin derivative on a DES.
The problem is that many antioxidants including those suitable for use on DESs are not particularly salutary to patients. This, together with the fact that, once fabricated and packaged in an essentially oxygen-free atmosphere protected from light, rapamycin derivative drugs are actually reasonably stable suggests that, in addition to in general reducing the exposure of the drug to harsh processing conditions, it would be beneficial to have an antioxidant present during the fabrication of a rapamycin derivative-containing DES but have a little as possible remaining once the DES is mounted on a carrier vehicle, sterilized and packaged in a light-tight, inert atmosphere container or once the DS has been implanted in a patient. The present invention provides a method of accomplishing this goal.